Investigating the Mechanism of Optic Nerve Hypoplasia Associated with CASK Mutation

 描述（由申请人提供）：视神经发育不全（ONH）是最常见的先天性视盘疾病之一，是儿童失明的一个日益普遍的原因。除了被认为是一种普遍的发育缺陷，ONH和自闭症谱系障碍（ASD）之间的关联已经建立。尽管ONH的发病率很高，但其分子和细胞机制尚不清楚。ONH的研究大多数是在视隔发育不良的背景下进行的，视隔发育不良与透明隔缺失和中线缺陷有关。在这里，我们确定了一种新的ONH小鼠模型，并建议使用它来阐明导致与疾病相关的表型的机制。具体来说，我们在CASK水平降低的小鼠中发现了ONH。CASK中的人类突变导致X连锁精神发育迟滞，其中一些患者属于ASD表型。受影响的患者通常表现为脑桥小脑发育不良和视神经发育不良/萎缩。CASK是突触粘附分子neurexin的特异性激酶，neurexin及其跨突触相互作用伙伴neuroligin的突变也与ASD相关。因此，研究CASK突变作为ONH的模型有可能提供ASD和ONH之间的分子联系。我们的初步数据表明，CASK杂合子敲除小鼠（+/-）表现出较薄的视神经轴突损失和星形胶质细胞增生的迹象。我们将使用动物遗传学，发育和成像研究，以了解ONH在这些小鼠的发病机制。具体来说，我们将分析轴突损失是原发性还是继发性的，视神经发育期间和之后CASK损失的细胞自主效应以及与ONH相关的精确细胞病理学。我们的建议有可能揭示ASD和ONH之间的分子联系。

 DESCRIPTION (provided by applicant): Optic nerve hypoplasia (ONH) is one of the most common congenital optic disc disorders and is an increasingly prevalent cause of childhood blindness. In addition to being considered a pervasive developmental defect, an association between ONH and autism spectrum disorder (ASD) has been established. Despite its prevalence, the molecular and cellular mechanisms leading to ONH is not clear. ONH is most studied in the context of septo-optic dysplasia which is associated with absent septum pellucidum and midline defects. Here, we identified a novel mouse model of ONH and propose to use it to elucidate mechanisms that lead to phenotypes associated with the disease. Specifically, we discovered ONH in mice with reduced levels of CASK. Human mutations in CASK lead to X-linked mental retardation with some of the patients falling within ASD phenotype. Affected patients often present with ponto-cerebellar hypoplasia and optic nerve hypoplasia/atrophy. CASK is a specific kinase for synaptic adhesion molecule neurexin, mutations in neurexin and its trans-synaptic interacting partner neuroligin also are associated with ASD. Thus investigating CASK mutation as a model of ONH has the potential to provide molecular link between ASD and ONH. Our preliminary data indicate that CASK heterozygous knockout mice (+/-) exhibit a thinner optic nerve with axonal loss and signs of astrogliosis. We will use animal genetics, developmental and imaging studies to understand pathogenesis of ONH in these mice. Specifically we will analyze whether the axonal loss are primary or secondary in nature, the cell autonomous effect of CASK loss during and after development of optic nerve and the precise cellular pathology that is associated with ONH. Our proposal has the potential to uncover a molecular link between ASD and ONH.